In drug addiction, the functioning of motivational and reward neural circuitry normally used to guide adaptive behaviors becomes biased towards continued drug abuse. These persistent neuroadaptive changes encompass alterations in molecular components at the synapse, changes in gene expression, and altered behavioral output. Even after cessation of drug intake, a large proportion of recovering drug addicts will relapse into drug abuse following weeks or months of abstinence (Kalivas and Volkow, 2005). One of the brain regions in which these changes take place is the prefrontal cortex (RFC), a critical region for goal- directed behaviors and impulse control. Imaging studies of addicts have revealed decreased basal activity during drug withdrawal (Goldstein and Volkow, 2001), and large increases in metabolic activity following exposure to drug cues in the PFC (Childress et al., 1999). It is a goal to correlate these functional modifications with altered molecular substrates to identify novel potential targets for therapeutic intervention. Examination of the PFC and regions that provide input to and output from the PFC following both acute and chronic drug exposure implicate changes in glutamate neurotransmission as a key factor in the addicted brain (McFarland and Kalivas, 2003). Increased branching and dysmorphic dendritic spines have been reported in the nucleus accumbens and PFC in rats one month after cessation of cocaine self administration (Robinson et al., 2001), however the molecular cascades underlying these responses have not been elaborated. This study will examine a cluster of dendritic mRNAs, identified by analysis of gene expression profiles in the PFC, that may contribute to the drug-induced synaptic plasticity in the PFC during a period of cocaine abstinence. These candidate genes, including staufen 2, and spinophilin, may underlie long-lasting physical modifications at the synapse. The overall goal of these studies is to yield insight into potential mechanisms that can be targeted to provide novel treatment opportunities for the prevention of drug abuse and relapse. The relevance of this research to public health is in gaining further understanding of the changes that occur in the brain in addiction. Knowing how long-term effects of drugs are stamped into the system even after drugs are no longer present may help generate new strategies for developing treatments to prevent drug abuse. [unreadable] [unreadable] [unreadable]